Geldanamycin (GM) is a benzoquinone ansamycin polylketide isolated from Streptomyces hygroscopicus. See DeBoer et al., Antibiot., 1970, 23, 442.

Although originally discovered by screening microbial extracts for antibacterial and antiviral activity, geldanamycin was later found to be cytotoxic to certain tumor cells. It is reported that geldanamycin exerts its antiproliferative and anti-cancer effect by binding with the heat shock protein 90 (Hsp90) chaperone and, in turn, altering the translocation properties of the tumor suppressor protein p53. See Stebbins et al., Cell, 1997, 239; Sepehrnia et al., J. Biol. Chem., 1996, 271, 15, 084; Dasgupta et al., Experimental Cell Research, 1997, 29, 237.
Inhibition of Hsp90 results in interference in multiple signaling pathways that mediate cancer growth and cell survival. Hsp90 is essential for the stability and function of several oncogenic proteins associated with key sites of genetic deregulation in human cancer. It is known to be over-expressed in human tumors and has the potential to inhibit the hallmark traits of cancer such as cell growth, signaling apoptosis avoidance, limitless proliferation, angiogenesis, and metastasis. See Sreedhar et al, Pharmacology & Therapeutics, 2004, 101, 227.
Geldanamycin was thought to exert its anti-cancerous effects by tight binding of the N-terminus pocket of Hsp90s. See Stebbins, C. et al., Cell, 1997, 89, 239. Further, ATP and ADP have both been shown to bind this pocket with low affinity and to have weak ATPase activity. See Proronlou, C. et al., Cell, 1997, 90, 65; Panaretou et al., EMBO J, 1998, 17, 4829. In vitro and in vivo studies have demonstrated that occupancy of this N-terminal pocket by geldanamycins and other Hsp90 inhibitors alters Hsp90 function and inhibits protein folding. At high concentrations, geldanamycins and other Hsp90 inhibitors have been shown to prevent binding of protein substrates to Hsp90 and to inhibit the ATP-dependent release of chaperone-associated protein substrates. See Scheibel et al., Proc. Nat'l. Acad. Sci. USA, 1999, 96, 1297. The geldanamycin-induced loss of these proteins leads to selective disruption of certain regulatory pathways and results in growth arrest at specific phases of the cell cycle. (See Muise-Heimericks et al., J Biol. Chem., 1998, 273, 29864), apoptosis, and/or differentiation of cells. See Vasilevskaya et al., Cancer Res., 1999, 59, 3935.
Recently, geldanamycin, as a specific inhibitor of Hsp90, was found to diminish specific wild-type p53 binding to the p21 promoter sequence. See McLean et al., Biochem Biophys Res Commun. 2004, 321(3), 665. Consequently, these inhibitors decrease p21 mRNA levels, which lead to a reduction in cellular p21/Waf1 protein, the latter being known to induce cell cycle arrest. A minor decrease in p53 protein levels following the treatment of human fibroblasts with the inhibitors suggests the potential involvement of Hsp90 in the stabilization of wild-type p53. More recently, geldanamycin was found to induce Hsp70 and prevent alpha-synuclein aggregation and toxicity in vitro. See McLean et al., Biochem Biophys Res Commun. 2004, 321(3), 665.
An important property of Hsp90 inhibitors is their ability to cause simultaneous combinatorial blockade of multiple cancer-causing pathways by promoting the degradation of many oncogenic client proteins. See Workman P., Trends Mol. Med. 2004 10(2), 47. Bedin et al. reported that geldanamycin induces MAPK-independent cell cycle arrest by inhibiting the chaperone function of the Hsp90 protein through competition for ATP binding. See Bedin et al., J. Int. J. Cancer 2004, 9(5), 43. The antiproliferative effect of geldanamycin has been attributed to destabilization of the Raf-1 protein, one of the targets of Hsp90, and to the resulting inhibition of MAPK. Li et al. found that geldanamycin exhibits broad-spectrum antiviral activity, including HSV-1 and severe acute respiratory syndrome coronavirus. Li et al., Antimicrob. Agents Chemother. 2004, 48(3), 867. HSV-1 replication in vitro was significantly inhibited by geldanamycin with a 50% inhibitory concentration of 0.093 μM which was also a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350 μM. The therapeutic index of geldanamycin was found to be over 3700.
Mandler et al. reported that conjugating geldanamycin to the anti-HER2 mAb Herceptin in targeted cancer therapy resulted in a greater antitumor effect than Herceptin alone. See Mandler et al. Cancer Res. 2004, 64(4), 1460. Geldanamycin also was to enhance the radiation sensitivity of human tumor cells by inhibiting the EGFR signal transduction system and the Akt signaling pathway. See Machida et al., Int. J. Radiat. Biol. 2003, 79(12), 973.
Despite its therapeutic potential as an anticancer agent, initial studies have indicated that the bioavailability of geldanamycin must be enhanced and the toxicity associated with the natural product reduced before significant progress can be made with respect to the therapeutic use of geldanamycin. The association of hepatotoxicity with the administration of geldanamycin led to its withdrawal from Phase I clinical trials. As with several other promising anticancer agents, geldanamycin also has poor water solubility that makes it difficult to deliver in therapeutically effective doses.
Analogues of geldanamycin have been synthesized in an attempt to increase the bioavailability and reduce the toxicity associated with the natural product. Among the more successful analogues is 17-allylaminogeldanamycin (17-AAG), which is currently in phase II clinical trials at the National Cancer Institute.

17-AAG has shown reduced hepatotoxicity while maintaining Hsp90 binding. This compound was selected for clinical studies based on its in vitro activity against chemorefractory tumors and novel biological actions. Like geldanamycin, 17-AAG has limited aqueous solubility. This property requires the use of a solubilizing carrier, most commonly Cremophore®, a polyethoxylated castor oil; however Cremophore® can produce serious side reactions in some patients.
A deficiency of the previous generation of ansamycins, such as geldanamycin and 17-AAG, is that they exhibit one or more poor pharmacological properties, e.g., metabolic instability, poor bioavailability, and/or difficult formulation ability, particularly for in vivo intravenous administration.
Therefore, there remains a need to prepare and synthesize anti-cancer compounds that allow for administration of doses significantly below the maximum tolerated dose while maintaining therapeutic effectiveness, as well as appropriate dosing schedules for combination therapy. The present invention provides these and other advantages.